We recently established the existence of SIV-specific MHC-E-restricted CD8+ T cells in rhesus macaques vaccinated with Rhesus cytomegalovirus vectors expressing SIV proteins (RhCMV/SIV). About 50% of rhesus macaques vaccinated with RhCMV exhibit robust control of viral replication and eventually clear virus entirely, constituting the first report of vaccine-mediated clearance of SIV. Thus, vaccines that mobilize MHC-E- restricted CD8+ T cells represent a novel and promising approach to vaccine development. However, understanding the extent to which macaque MHC-E mirrors HLA-E in humans is critical to establishing a reliable non-human primate model of HLA-E-restricted CD8+ T cell responses. In this project, we aim to characterize MHC-E as a restricting molecule for CD8+ T cell responses in macaques. First, we will investigate whether MHC-E sequence diversity impacts function by comparing the antigen binding and presentation abilities of multiple human and macaque MHC-E molecules. Second, we will move the CMV-based SIV vaccine approach into the Mauritian cynomolgus macaque model, where MHC-E genetics is more similar to that of humans. Successful completion of this research will result in the first detailed analysis of macaque MHC-E as a restricting molecule for CD8+ T cells, and will ultimately gauge the strength of two macaque models of HLA-E-restricted CD8+ T cells.